Process for the separation of transoestradiol and product obtained thereby



' other oestrogenic Patented Oct. 27, 1942 UNITED STATES PATENT OFFICE2,300,134 PROCESS FOR THE SEPARATION OI Ms- OEIOL AND PRODUCT OBTAINED{If- 1:

mm. mm. more, 'leltow,

mum to Bob near Berlin,

Bloomfield, N. 1., a corporation or New Jersey No Dra No. 317,887. In

wing. Application February 8, 1040 German January 11, im

13 Claims. (CL M91 and Logemann, Serial No. 203,822, filed April 23,1938).

I have found that trans-oestradiol can be separated not only fromcis-oestradiol, but also from equilenin, di-hydro-equilln, anddi-hydro-equilenin, in more simple fashion than by precipitation bymeans of alkaloids or saponins, and can be isolated in good yield in theform of a product of very high purity by converting it, by

area, into a dimcultly soluble compound in the ed with as saturated anaqueous urea solution as possible, and from the so-obtained reactionproduct the active substances which did not react with The so-obtainedtrans-oestradiol-urea com pound is almost insoluble in a cold saturatedurea solution in water, or in organic solvents miscible with water, suchas methyl alcohol, ethyl alcohol,

soasisobtainedbythehy From the solution of the residual hormones rem themanufacture oi' the trans-oesaqueous soluit has been found that bytreatment with wa- 15 ter, a part or the oestrogenic substances PassesThese active substances have the property oi dissolving in water even inthe cold and 01' thereby yielding aqueous, injectible hormone solutionswith 1000 R.U./cc. and higher.

The mu example will serve to illustrate the invention more in detail:

Example 5.0 g. of a mixture of oestrogenic dlols, such drogenation of acrude oestrone obtained from which were present in the starting materialand which can be separated by fractional distillation. crystallization,sublimation, or in other known ways.

The residue obtained by evaporating the alcoholic mother liquor todryness and containing the residual hormones can be freed from urea alsoby treatment with water. Surprisingly, it has been found thata part ofthe residual hormones goes into solution. If a salt, such as ammoniumsulphate and the like, is added to these aqueous solutions, there isprecipitated an active oestrogenic material which dissolves in water andyields aqueous injectible hormone solutions having a potency of 1000R.U./cc. and even higher.

It will be obvious that myprocess is applicable to oestrogenic mixturesof any origin containing trans-oestradiol, and that variations from thespecific proportions and procedures above set forth may be resorted towithin the scope of the appended claims without departing from thespirit of the invention.

I claim:

1. Process for the separation of transoestradiol from oestrogenicmixtures containing the same, comprising converting the transoestradiolinto its diflicultly soluble urea compound, and separating such compoundfrom the other components of the mixture.

2. Process 'for the separation of transoestradiol from oestrogenicmixtures containing the same, comprising dissolving the starting mixturein a hot solution of urea in an organic solvent, separating out thetrans-oestradiol-urea compound precipitating on cooling, and thereaftersplitting such compound into its components. I

3. Process for the oestradiol from oestrogenic mixtures containing thesame, comprising dissolving a mixture of follicular hormones containingtrans-oestradiol in a hot solution of urea in an organic solvent,separating out the trans-oestradiol-urea comseparation of transpoundprecipitating on cooling, and. thereafter splitting such compound intoits components.

4. Process according to claim 1, wherein the mixture is treated with asolution of urea in methyl alcohol.

5. Process for the separation 01': transoestradiol from oestrogenicmixtures containing the same, comprising adding urea to a solution ofthe starting material up to saturation, separating the precipitatedtrans-oestradiol-urea compound, and decomposing it into its components.

6. Process for the separation of transoestradiol from oestrogenicmixtures containing solvent which the same, comprising adding urea toa'heated solution of a mixture of follicular hormones, containingtrans-oestradiol, up to saturation, allowing the solution to cool,separating the precipitated trans-oestradiol-urea from the solution ofthe remaining hormones,-and splitting the urea I compound into itscomponents.

'1. Process for the separation of transoestradiol from oestrogenicmixtures containing the same, comprising treating the starting materialwith an aqueous solution of a urea, extracting from the obtainedreaction mixture the unreacted substances with the aid of an organic isnon-miscible with water and is a non-solvent for urea, and thendecomposing the undissolved trans-oestradiol-urea compound into itscomponents.

8. Process for the separation of transoestradiol from oestrogenicmixtures containing the same, comprising converting the transoestradiolinto its diificultly soluble urea compound, separating such compoundfrom the other components of the mixture, and decomposing the separatedtrans-oestradiol' urea compound by treatment with warm water.

9. Process for the separation of transoestradiol from oestrogenicmixtures containing the same, comprising dissolving the mixture in anorganic solvent, converting the transoestradiol into its diflicultlysoluble urea compound, separating such compound from the othercomponents of the mixture, evaporating the organic solvent from themother liquor containing the residual substances, and removing excessurea from the residue by treatment with an aqueous medium.

10. Process according to claim 9, wherein the excess urea is removedfrom the residue by treatment with a relatively large quantity of water.

11. Process according to claim 9, wherein the excess urea is removedfrom the residue by treatment with an aqueous salt solution.

12. Process for the separation of transoestradiol from oestrogenicmixtures containing the same, comprising preparing a solution of amixture of follicle hormones containing transoestradiol, converting thetrans-oestradiol contained in the mixture into its difflcultly solubleurea compound, separating such compound from the other components of themixture, treating the residual hormones with water, and isolating fromthe urea solution so obtained an active oestrogenic material.

13. A trans-oestradiol-urea compound.

HANS PRIEWE.

